Elucidation of the decades? long period of time during which Alzheimer disease (AD) pathologies begin to develop prior to the appearance of cognitive symptoms (i.e., ?preclinical? AD) has been largely driven by the study of disease biomarkers. Such biomarkers are now being used to more precisely define various stages within this preclinical period in order to better understand the pathologic processes taking place during this early stage and to better inform the design and interpretation of prevention trials aimed at identifying diseasemodifying therapies that have the best chance of preserving normal cognitive function. Data from ACS Project 2 contributed to the finding that preclinical AD (defined by CSF biomarkers) in older individuals (? 65 yrs) increases the risk for developing symptomatic AD in a stage-dependent manner. In addition, changes in amyloid-related markers (A42) over time were observed in early middle-aged participants (45-64 yrs), whereas changes in tau and ptau181 were observed in those in mid middle-age (55-64 yrs) and coincided with initial declines in cognition. As the current ACS cohort is aging, we are now poised to evaluate biomarker trajectories in individuals as they progress from being biomarker-negative to biomarker-positive (preclinical AD) to cognitively impaired (symptomatic AD). The proposed experiments are designed to evaluate the utility of CSF markers for identifying those individuals with preclinical AD who are in the transition period from cognitive normality to impairment. Novel markers of synaptic dysfunction will be evaluated in addition to the traditional markers of core AD pathologies. CSF tau and ptau181 will be compared with tau PET imaging to validate their utility as presumed markers of neurofibrillary tangles. Finally, in an exploratory aim, we will utilize the innovative method of Stable Isotope Labeling Kinetics (SILK) pioneered by Dr. Randall Bateman to evaluate the potential of a plasma (and CSF) A kinetic measure as an indicator of brain amyloid pathology. Aim 1. Continue to measure CSF concentrations of A40, A42, tau, ptau181, YKL-40, and VILIP-1, as well as novel markers of synaptic dysfunction, Neurogranin and SNAP-25. Aim 2. In longitudinal analyses, assess the annual rate of change in CSF biomarker concentrations as a function of AD risk (age, family history, APOE?4 status) and their relationships with baseline and future rates of change in other CSF markers. Aim 3. Correlate fluid biomarker measures (and rate of change over time) with clinical and psychometric performance (Clinical Core), novel tau imaging as assessed by T807 PET (Project 1), attentional control measures (Project 3), and structural neuroimaging (via MRI) and amyloid PET (via florbetapir) (Project 4). Aim 4. Evaluate the utility of A isotope kinetics (using stable isotope labeling kinetics methods [SILK]) in CSF and plasma as indicators of the presence/absence of brain amyloid.